Reagents such as retroviruses or single doses of alkylating agents have revealed basic mechanisms of oncogenesis. However, the molecular details of the link between carcinogen and tumor are not known for any human cancer. In the case of non-melanoma skin cancer, this information includes the identity of the genes frequently mutated by sunlight and the role of various sunlight wavelengths in causing these mutations. Non-melanoma skin cancers provide an opportunity to link sunlight to its genetic effect, because directly-absorbed ultraviolet light leaves a mutational signature distinct from other carcinogens. CC -> TT transitions are virtually unique to UV; in addition, most other UV-induced mutations are C -> T transitions at dipyrimidine sites. These mutations would reveal both the target genes and their mutagen. In our preliminary studies, we found CC-> TT and C -> T mutations in the p53 tumor suppressor gene in at least 40% of human squamous cell carcinomas of skin. We propose to: 1) Use the polymerase chain reaction to examine the p53 gene for sunlight-related mutations in a putative precursor lesion, actinic keratosis; a non-metastasizing keratinocyte tumor, basal cell carcinoma; and a melanocyte tumor with a clear sunlight etiology; lentigo maligna melanoma. Tumors from xeroderma pigmentosum patients will be examined to distinguish misrepair mutations from misreplication mutations. 2) Examine similarly the FOS gene and regulatory regions of the H, K, and N RAS genes. 3) Examine the p53 and retinoblastoma genes for loss of alleles, which can be caused by long-wavelength UV components of sunlight. These studies will help elucidate the mechanisms by which sunlight UV interacts with DNA to eventually lead to sunlight-related cancers. It will provide information on the effective UV wavelengths, the genes in which the light is absorbed, the DNA photoproducts, the types of mutations, the nucleotides involved, and possible hotspot sequences.